Effects of Intermittent Fasting on Health, Aging, and Disease or weight loss.2-5 Instead, intermittent

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  • T h e n e w e ngl a nd j o u r na l o f m e dic i n e

    n engl j med 381;26 nejm.org December 26, 2019 2541

    Review Article

    From the Translational Gerontology Branch (R.C.) and the Laboratory of Neurosci- ences (M.P.M.), Intramural Research Pro- gram, National Institute on Aging, National Institutes of Health, and the Department of Neuroscience, Johns Hopkins Univer- sity School of Medicine (M.P.M.) — both in Baltimore. Address reprint requests to Dr. Mattson at the Department of Neuro- science, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, or at mmattso2@ jhmi . edu.

    This article was updated on December 26, 2019, at NEJM.org.

    N Engl J Med 2019;381:2541-51. DOI: 10.1056/NEJMra1905136 Copyright © 2019 Massachusetts Medical Society.

    According to Weindruch and Sohal in a 1997 article in the Journal, reducing food availability over a lifetime (caloric restriction) has remark-able effects on aging and the life span in animals.1 The authors proposed that the health benefits of caloric restriction result from a passive reduction in the production of damaging oxygen free radicals. At the time, it was not generally recognized that because rodents on caloric restriction typically consume their entire daily food allotment within a few hours after its provision, they have a daily fasting period of up to 20 hours, during which ketogenesis occurs. Since then, hundreds of studies in animals and scores of clinical studies of controlled intermittent fasting regimens have been conducted in which metabolic switching from liver-derived glucose to adipose cell–derived ketones occurs daily or several days each week. Although the magnitude of the effect of intermittent fasting on life-span extension is variable (influenced by sex, diet, and genetic factors), studies in mice and nonhuman primates show consistent effects of caloric restriction on the health span (see the studies listed in Section S3 in the Supplementary Appen- dix, available with the full text of this article at NEJM.org).

    Studies in animals and humans have shown that many of the health benefits of intermittent fasting are not simply the result of reduced free-radical production or weight loss.2-5 Instead, intermittent fasting elicits evolutionarily conserved, adaptive cellular responses that are integrated between and within organs in a manner that improves glucose regulation, increases stress resistance, and sup- presses inflammation. During fasting, cells activate pathways that enhance intrin- sic defenses against oxidative and metabolic stress and those that remove or repair damaged molecules (Fig. 1).5 During the feeding period, cells engage in tissue- specific processes of growth and plasticity. However, most people consume three meals a day plus snacks, so intermittent fasting does not occur.2,6

    Preclinical studies consistently show the robust disease-modifying efficacy of intermittent fasting in animal models on a wide range of chronic disorders, in- cluding obesity, diabetes, cardiovascular disease, cancers, and neurodegenerative brain diseases.3,7-10 Periodic flipping of the metabolic switch not only provides the ketones that are necessary to fuel cells during the fasting period but also elicits highly orchestrated systemic and cellular responses that carry over into the fed state to bolster mental and physical performance, as well as disease resistance.11,12

    Here, we review studies in animals and humans that have shown how intermit- tent fasting affects general health indicators and slows or reverses aging and disease processes. First, we describe the most commonly studied intermittent- fasting regimens and the metabolic and cellular responses to intermittent fasting. We then present and discuss findings from preclinical studies and more recent clinical studies that tested intermittent-fasting regimens in healthy persons and in

    Dan L. Longo, M.D., Editor

    Effects of Intermittent Fasting on Health, Aging, and Disease

    Rafael de Cabo, Ph.D., and Mark P. Mattson, Ph.D.

    The New England Journal of Medicine Downloaded from nejm.org at RICE UNIVERSITY on December 27, 2019. For personal use only. No other uses without permission.

    Copyright © 2019 Massachusetts Medical Society. All rights reserved.

  • n engl j med 381;26 nejm.org December 26, 20192542

    T h e n e w e ngl a nd j o u r na l o f m e dic i n e

    patients with metabolic disorders (obesity, insu- lin resistance, hypertension, or a combination of these disorders). Finally, we provide practical information on how intermittent-fasting regi- mens can be prescribed and implemented. The practice of long-term fasting (from many days to weeks) is not discussed here, and we refer inter- ested readers to the European clinical experi- ence with such fasting protocols.13

    In ter mi t ten t Fa s ting a nd Me ta bolic S w i t ching

    Glucose and fatty acids are the main sources of energy for cells. After meals, glucose is used for energy, and fat is stored in adipose tissue as

    triglycerides. During periods of fasting, triglycer- ides are broken down to fatty acids and glycerol, which are used for energy. The liver converts fatty acids to ketone bodies, which provide a major source of energy for many tissues, espe- cially the brain, during fasting (Fig. 2). In the fed state, blood levels of ketone bodies are low, and in humans, they rise within 8 to 12 hours after the onset of fasting, reaching levels as high as 2 to 5 mM by 24 hours.14,15 In rodents, an eleva- tion of plasma ketone levels occurs within 4 to 8 hours after the onset of fasting, reaching milli- molar levels within 24 hours.16 The timing of this response gives some indication of the ap- propriate periods for fasting in intermittent- fasting regimens.2,3

    In humans, the three most widely studied intermittent-fasting regimens are alternate-day

    Figure 1. Cellular Responses to Energy Restriction That Integrate Cycles of Feeding and Fasting with Metabolism.

    Total energy intake, diet composition, and length of fasting between meals contribute to oscillations in the ratios of the levels of the bioenergetic sensors nicotin- amide adenine dinucleotide (NAD+) to NADH, ATP to AMP, and acetyl CoA to CoA. These intermediate energy carriers activate downstream proteins that regulate cell function and stress resistance, including transcription factors such as forkhead box Os (FOXOs), peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), and nuclear factor erythroid 2–related factor 2 (NRF2); kinases such as AMP kinase (AMPK); and deacetylases such as sirtuins (SIRTs). Intermittent fasting triggers neuroendocrine responses and adaptations character- ized by low levels of amino acids, glucose, and insulin. Down-regulation of the insulin–insulin-like growth fac- tor 1 (IGF-1) signaling pathway and reduction of circu- lating amino acids repress the activity of mammalian target of rapamycin (mTOR), resulting in inhibition of protein synthesis and stimulation of autophagy. During fasting, the ratio of AMP to ATP is increased and AMPK is activated, triggering repair and inhibition of anabolic processes. Acetyl coenzyme A (CoA) and NAD+ serve as cofactors for epigenetic modifiers such as SIRTs. SIRTs deacetylate FOXOs and PGC-1α, resulting in the expression of genes involved in stress resistance and mitochondrial biogenesis. Collectively, the organism responds to intermittent fasting by minimizing anabolic processes (synthesis, growth, and reproduction), favor- ing maintenance and repair systems, enhancing stress resistance, recycling damaged molecules, stimulating mitochondrial biogenesis, and promoting cell survival, all of which support improvements in health and disease resistance. The abbreviation cAMP denotes cyclic AMP, CHO carbohydrate, PKA protein kinase A, and redox reduction–oxidation.

    Intermittent fasting and caloric restriction

    FatCHO

    NADH NAD+

    Redox signaling

    Protein

    mTOR SIRTs

    SIRTs

    FOXOs PGC-1α

    Acetyl CoA:CoA

    Mitochondria

    Cytoplasm

    Nucleus

    Rough endoplasmic

    reticulum

    Glucose or lipid metabolism

    Health and stress resistance

    Proteostasis and autophagy

    Stress resistance

    Mitochondrial biogenesis

    Cell survival

    NRF2

    ATP:AMP

    cAMP or PKA

    Neuroendocrine signalingNutrients

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    Effects of Intermittent Fasting on Health and Aging

    fasting, 5:2 intermittent fasting (fasting 2 days each week), and daily time-restricted feeding.11

    Diets that markedly reduce caloric intake on 1 day or more each week (e.g., a reduction to 500 to 700 calories per day) result in elevated levels of ketone bodies on those days.17-20 The metabolic switch from the use of glucose as a fuel source to the use of fatty acids and ketone bodies re- sults in a reduced respiratory-exchange ratio (the ratio of carbon dioxide produced to oxygen con- sumed), indicating the greater metabolic flexi- bility and efficiency of energy production from fatty acids and ketone bodies.3

    Ketone bodies are not just fuel used during periods of fasting; they are potent signaling molecules with major effects on cell and organ functions.21 Ketone bodies regulate the expres- sion and activity of many proteins and mo